Abstract

Purpose: The heat shock protein 90 (Hsp90) plays an important role in chaperoning oncogenic client proteins in multiple myeloma (MM) cells, and several Hsp90 inhibitors have shown anti-tumor activities both in vitro and vivo. However the precise mechanism of action of Hsp90 inhibitor in MM has not been fully elucidated.
Experimental Design: We evaluated the anti-tumor activities of KW-2478, a non-ansamycin Hsp90 inhibitor, in MM cells with various chromosomal translocations of immunoglobulin heavy chain (IgH) loci both in vitro and vivo.
Results: Our studies revealed that exposure of KW-2478 to MM cells resulted in growth inhibition and apoptosis which were associated with degradation of well-known client proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, Cyclin D1) and FGFR3 was shown to be a new client protein of Hsp90 chaperon-complex. In addition, KW-2478 depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and Cyclin D1 expression. In NCI-H929 subcutaneously inoculated model, KW-2478 showed a significant suppression of tumor growth, and induced the degradation of client proteins in tumors. Furthermore, in a novel orthotopic MM model of intravenously inoculated OPM-2/GFP, KW-2478 showed a significant reduction of both serum M-protein and MM tumor burden in the bone marrow.
Conclusions: These results suggest that targeting such diverse pathways by KW-2478 could be a promising strategy for the treatment of MM with various cytogenetic abnormalities.